Project Summary How axons are selectively ensheathed by specific amounts of myelin is a fundamental and unsolved problem in neurobiology. Myelin, produced by oligodendrocytes in the central nervous system of vertebrate animals, enhances axonal conduction of electrical impulses and provides axons with metabolic support. Evidence accumulated over the past several years indicates that myelination can adapt to neuronal activity, and that adaptive myelination is essential for learning and new skill development. The next important step is to identify the molecular functions that mediate communication between neurons and oligodendrocytes to facilitate adaptive myelination. Building on our own evidence that activity-evoked axonal vesicular secretion promotes myelin sheath growth, we hypothesize that proteins that function in synaptic communication between neurons also mediate synaptic-like signaling between axons and oligodendrocytes. We will test this hypothesis using zebrafish and mice, building on our expertise in zebrafish genome modification, mouse in utero electroporation and imaging of oligodendrocyte lineage cells in both species. Our experimental plan has two parts. First, we will investigate the expression and subcellular localization of synaptic proteins identified by RNA-seq profiling of oligodendrocyte lineage cell transcripts. Second, we will initiate loss-of-function studies to learn if synaptic proteins promote myelin sheath growth in vivo. This project has the potential to reveal important new mechanistic insights to adaptive myelination and the results will create a foundation for future, detailed investigations of axon- oligodendrocyte communication.